title: Pharmacokinetics of the amidine prodrug of a novel oral anticoagulant factor VIIa inhibitor (AS1924269-00) in rats.
abstract: AS1924269-00 is a promising orally applicable anticoagulant that inhibits FVIIa but has very low oral absorption. Therefore, in this study, we aimed to develop a prodrug of AS1924269-00, which possesses a carbamate-added amidine functional group, with high membrane permeability. We investigated the pharmacokinetics of the carbamate-type prodrug of AS1924269-00 in rats. The Caco-2 cell monolayer was used as an in vitro model and in parallel an artificial membrane permeability assay (PAMPA) was performed to examine the transport mechanisms of the prodrug. The bioavailability of the active form was determined to be only 0.3% in rats, but the oral absorption of the prodrug was markedly improved, and its bioavailability was 36%. Our in vivo result was consistent with the finding that compared to AS1924269-00, the prodrug showed favorable permeability in Caco-2 cells and PAMPA. We introduced carbamate into the amidine functional group of the FVIIa inhibitor, which possesses the amidine backbone, and converted it to a prodrug using carboxylic acid ethyl ester. This novel prodrug had favorable absorption and membrane permeability in vivo and in vitro. Thus, we suggest a clinical application of the carbamate-added amidine prodrug of the FVIIa inhibitor.
authors.affiliation: Pharmacokinetics Research Laboratories, Kissei Pharmaceutical Co., Ltd., Nagano, Japan. takeshi_nakabayashi@pharm.kissei.co.jp
authors.forename: T
authors.initials: T
authors.lastname: Nakabayashi
authors.forename: Y
authors.initials: Y
authors.lastname: Gotoh
authors.forename: N
authors.initials: N
authors.lastname: Kamada
authors.forename: M
authors.initials: M
authors.lastname: Fujioka
authors.forename: T
authors.initials: T
authors.lastname: Ishihara
authors.forename: A
authors.initials: A
authors.lastname: Hirabayashi
authors.forename: H
authors.initials: H
authors.lastname: Sato
mesh_terms: D000578:Amidines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018938:Caco-2 Cells; D002851:Chromatography, High Pressure Liquid; D015942:Factor VIIa / Q000037:antagonists & inhibitors*; D006207:Half-Life; D006801:Humans; D007202:Indicators and Reagents; D008297:Male; D013058:Mass Spectrometry; D008567:Membranes, Artificial; D010539:Permeability; D010642:Phenoxyacetates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C582355:AS1924269-00; D000578:Amidines; D000925:Anticoagulants; D007202:Indicators and Reagents; D008567:Membranes, Artificial; D010642:Phenoxyacetates; D015942:Factor VIIa